15-34257712-C-T

Variant names:

• chr15-34257712-C-T
• rs1555381416
• NM_001365088.1:c.620G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001365088.1(SLC12A6):​c.620G>A​(p.Arg207His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A6 NM_001365088.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91
• Publications: 3 publications found

Genes affected

SLC12A6 (HGNC:10914): (solute carrier family 12 member 6) This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

SLC12A6 Gene-Disease associations (from GenCC):

• agenesis of the corpus callosum with peripheral neuropathy

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease, axonal, IIa 2II

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000259468 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-34257713-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5331.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 15-34257712-C-T is Pathogenic according to our data. Variant chr15-34257712-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 521402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365088.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	NM_001365088.1	MANE Select	c.620G>A	p.Arg207His	missense	Exon 6 of 26	NP_001352017.1	Q9UHW9-1
	SLC12A6	NM_133647.2		c.620G>A	p.Arg207His	missense	Exon 5 of 25	NP_598408.1	Q9UHW9-1
	SLC12A6	NM_001042496.2		c.593G>A	p.Arg198His	missense	Exon 6 of 26	NP_001035961.1	Q9UHW9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.620G>A	p.Arg207His	missense	Exon 6 of 26	ENSP00000346112.3	Q9UHW9-1
	SLC12A6	ENST00000560611.5	TSL:1	c.620G>A	p.Arg207His	missense	Exon 5 of 25	ENSP00000454168.1	Q9UHW9-1
	SLC12A6	ENST00000558589.5	TSL:1	c.593G>A	p.Arg198His	missense	Exon 6 of 26	ENSP00000452776.1	Q9UHW9-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Charcot-Marie-Tooth disease, axonal, IIa 2II (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.83		Loss of stability (P = 0.0792)
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.71
gMVP		0.95
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555381416; hg19: chr15-34549913; COSMIC: COSV51622808; COSMIC: COSV51622808;